Bi Yanming, Stuelten Christina H, Kilts Tina, Wadhwa Sunil, Iozzo Renato V, Robey Pamela G, Chen Xiao-Dong, Young Marian F
Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
J Biol Chem. 2005 Aug 26;280(34):30481-9. doi: 10.1074/jbc.M500573200. Epub 2005 Jun 17.
Extracellular matrix glycoproteins and proteoglycans bind a variety of growth factors and cytokines thereby regulating matrix assembly as well as bone formation. However, little is known about the mechanisms by which extracellular matrix molecules modulate osteogenic stem cells and bone formation. Using mice deficient in two members of the small leucine-rich proteoglycans, biglycan and decorin, we uncovered a role for these two extracellular matrix proteoglycans in modulating bone formation from bone marrow stromal cells. Our studies showed that the absence of the critical transforming growth factor-beta (TGF-beta)-binding proteoglycans, biglycan and decorin, prevents TGF-beta from proper sequestration within the extracellular matrix. The excess TGF-beta directly binds to its receptors on bone marrow stromal cells and overactivates its signaling transduction pathway. Overall, the predominant effect of the increased TGF-beta signaling in bgn/dcn-deficient bone marrow stromal cells is a "switch in fate" from growth to apoptosis, leading to decreased numbers of osteoprogenitor cells and subsequently reduced bone formation. Thus, biglycan and decorin appear to be essential for maintaining an appropriate number of mature osteoblasts by modulating the proliferation and survival of bone marrow stromal cells. These findings underscore the importance of the micro-environment in controlling the fate of adult stem cells and reveal a novel cellular and molecular basis for the physiological and pathological control of bone mass.
细胞外基质糖蛋白和蛋白聚糖可结合多种生长因子和细胞因子，从而调节基质组装以及骨形成。然而，关于细胞外基质分子调节成骨干细胞和骨形成的机制，人们了解甚少。利用缺乏富含亮氨酸小分子蛋白聚糖中的两个成员，即双糖链蛋白聚糖和核心蛋白聚糖的小鼠，我们发现了这两种细胞外基质蛋白聚糖在调节骨髓基质细胞骨形成中的作用。我们的研究表明，关键的转化生长因子-β（TGF-β）结合蛋白聚糖双糖链蛋白聚糖和核心蛋白聚糖的缺失，会阻止TGF-β在细胞外基质中被适当隔离。过量的TGF-β直接与其在骨髓基质细胞上的受体结合，并过度激活其信号转导途径。总体而言，bgn/dcn缺陷型骨髓基质细胞中TGF-β信号增加的主要影响是从生长到凋亡的“命运转变”，导致骨祖细胞数量减少，进而骨形成减少。因此，双糖链蛋白聚糖和核心蛋白聚糖似乎对于通过调节骨髓基质细胞的增殖和存活来维持适当数量的成熟成骨细胞至关重要。这些发现强调了微环境在控制成体干细胞命运中的重要性，并揭示了骨量生理和病理控制的新细胞和分子基础。
